Precision Particle Fabrication-enabled Betamethasone-loaded Microspheres for Tran

描述(由申请人提供)：目前治疗突发性感音神经性耳聋(SSNHL)的方法不能在足够长的时间内将内耳药物浓度维持在适当的治疗窗口内以达到治疗效果。一种新型的长期、可控释放糖皮质激素到内耳的给药系统将极大地改善SSNHL的治疗方案。我们提出的策略使用精密颗粒制造(PPF)技术来制备倍他米松微球，用于经鼓室注射、圆窗膜(RWM)定位和内耳缓释。我们方法的核心优势是PPF技术允许精确控制颗粒大小、形状、材料和释放速率。我们的长期目标是使PPF-倍他米松微球经鼓室输送成为SSNHL患者的标准护理。我们假设微球可以在RWM上保留两周，倍他米松的释放量可以维持在治疗量(~55 ng/天)的25%以内。我们预计，这种新的方法将使倍他米松在内耳的治疗浓度保持在一定水平，这将大大提高SSNHL治疗的安全性和有效性，而不是目前可用的选择。我们的研究团队将首先开发和表征微球大小和倍他米松释放曲线之间的关系，以确定实现内耳长期控释的可行性(目标1)。然后，我们将确定最佳微球固定化策略，使RWM定位至少14天，毒性最小(目标2)。其结果将是微球维持准确的倍他米松剂量，并与RWM附着足够长的时间。在确定这种方法的可行性后，我们将在第二阶段展示我们有能力在小(鼠)和大(羊)动物模型中精确控制内耳倍他米松浓度的药代动力学曲线。这种PPF支持的药物传递策略解决了剂量准确性和长期释放的问题。此外，基于PPF的胶囊具有很强的适应性，可以作为多种药物类别的跨鼓室给药平台。这一独特的策略有很大的潜力成为SSNHL治疗的标准护理。 公共卫生相关性：目前治疗突发性感音神经性耳聋(SSNHL)的方法不能在足够长的时间内将内耳药物浓度维持在适当的治疗窗口内以达到治疗效果。一种新型的长期、可控释放糖皮质激素到内耳的给药系统将极大地改善SSNHL的治疗方案。我们提出的策略使用精密粒子制造(PPF)来设计糖皮质激素负载微球，其设计保持在内耳的圆形窗膜上，并在整个治疗期间提供可控和持续的治疗释放。

DESCRIPTION (provided by applicant): Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to create betamethasone-loaded microspheres for transtympanic injection, round window membrane (RWM) localization, and sustained-release to the inner ear. The central advantage of our approach is that PPF technology allows for precise control of particle size, shape, material, and release rates. Our long-term goal is for transtympanic delivery of PPF-enabled betamethasone-loaded microspheres to be the standard-of-care for people who suffer from SSNHL. We hypothesize that microspheres can be retained on the RWM for two weeks and that betamethasone release can be maintained within 25% of a therapeutic dose (~55 ng/day). We expect that this novel approach will enable sustained levels of therapeutic concentrations of betamethasone to the inner ear that will dramatically improve the safety and efficacy of SSNHL treatments over currently available options. Our research team will first develop and characterize the relationship between the microsphere size and betamethasone release profiles to establish the feasibility of achieving long-term, controlled release to the inner ear (Aim 1). We will then determine the optimal microsphere immobilization strategy to enable RWM localization for a minimum of 14 days with minimal toxicity (Aim 2). The result will be microspheres that sustain a precise betamethasone dose and adhere to the RWM for sufficient time. After establishing the feasibility of this approach, we will, in Phase II, demonstrate our ability to precisely control the pharmacokinetic profile of inner ear betamethasone concentrations in small (mouse) and large (sheep) animal models. This PPF- enabled drug-delivery strategy addresses issues of dosage accuracy and long-term release. In addition, PPF- based encapsulation is highly adaptable and can serve as a transtympanic delivery platform for multiple drug classes. This unique strategy has significant potential to become the standard-of-care for treatment of SSNHL. PUBLIC HEALTH RELEVANCE: Current approaches to treat sudden sensorineural hearing loss (SSNHL) do not maintain inner ear drug concentrations within an appropriate therapeutic window for sufficient lengths of time to achieve therapeutic effect. A novel delivery system for long-term, controlled release of glucocorticoid steroids to the inner ear would constitute a dramatic improvement in SSNHL treatment options. Our proposed strategy uses Precision Particle Fabrication (PPF) to engineer glucocorticoid-loaded microspheres that are designed to remain localized to the round-window membrane of the inner ear and provide controlled and sustained release of the therapeutic throughout the treatment period.